There remains a clear and imperative need for new and more effective cancer drugs. In an effort to meet this need, the broad, long-term goals of this program are to use sophisticated, whole-cell and molecular-based screening methods to identify novel cancer leads from unexplored marine invertebrates and cultured marine microorganisms. Active molecules will be structurally characterized and rapidly moved into in vivo studies and towards clinical development in collaboration with the Oncology Drug Discovery Group at Bristol-Myers Squibb (BMS) and the National Cancer Institute (NCI). In addition to discovering new molecules with novel mechanisms of action and demonstrable anti-cancer activities, a specific aim of this renewal application is to continue the development of 12 preclinical anti-cancer drug lad leads discovered as part of the current award. The proposed research is designed to access unstudied, chemically rich marine invertebrates and microorganisms collected during expeditions to South Africa and various US territories including Guam and Alaskan coastal waters. Extracts of marine organisms will be submitted to BMS for high through put screening (HTS) in proprietary, cancer-relevant screens and mechanistically predictive biochemical and receptor-based models. Active extracts will be subjected to BMS and NCI for mechanisms for action studies, in vitro testing against diverse cancer cell types, in vivo animal model and, ultimately, clinical studies. In addition, a new component of this program will be the fractionation of crude extracts and the submission of the resulting semi-pure materials for HTS. The aim of the invertebrate component of this program will be to target rare and unstudied ascidians, soft corals, and bryozoans, representing taxonomic groups with a proven history of containing unusual biologically active metabolites. The majority of our efforts however will be focused on taxonomically diverse marine microorganisms representing both higher (filamentous) and lower (zoosporic) fungi and bacteria that display gliding motility. The source of these microorganisms will be unique deep sea sediments available through Scripps and invertebrates obtained during collecting expeditions.